Surgical errors and complications following cesarean delivery in the United States.

BACKGROUND: Cesarean delivery is the most common inpatient surgery performed internationally. Although cesarean delivery is typically performed to prevent adverse maternal and fetal outcomes, there is still a risk of surgical errors and complications. This study examined maternal and hospital risk factors associated with errors and complications following cesarean delivery in the United States. OBJECTIVE: To determine the prevalence of, and associated individual- and hospital-level risk factors for, surgical errors and complications following cesarean delivery in the United States. MATERIALS AND METHODS: Data were obtained from the 2012-2014 National Inpatient Sample. Surgical errors (eg,. foreign body retained during surgery, anesthetic error) can be the result of human error, whereas complications (eg, mortality, postpartum hemorrhage) can be due to external factors such as pre-existing comorbidities. The overall prevalence of surgical errors and complications in cesarean delivery was calculated. Multilevel logistic regression models were used to examine the association between individual and hospital characteristics and surgical errors/complications. RESULTS: Among 648,584 cesarean delivery hospitalizations, 1.98% (95% confidence interval, 1.95-2.01%) and 8.43% (95% confidence interval, 8.40-8.46%) of women had an error or complication, respectively. The most common errors were anesthetic errors, errors involving blood vessels, and errors involving the bladder. The most common complications were postpartum hemorrhage, infection, and hysterectomy. Both individual- and hospital-level factors were associated with errors and complications. Women with Medicaid insurance had increased odds of errors (odds ratio, 1.40; 95% confidence interval, 1.37-1.43) but lower odds of complications (odds ratio, 0.89; 95% confidence interval, 0.88-0.90) compared to women with private insurance. Compared to non-Hispanic white women, women of all races had lower odds of error, and only non-Hispanic black women had greater odds of complications (odds ratio, 1.14; 95% confidence interval, 1.13-1.16). Similarly, rural hospitals had lower odds of surgical errors (odds ratio, 0.59; 95% confidence interval, 0.56-0.62) and complications (odds ratio, 0.61; 95% confidence interval, 0.59-0.62), whereas hospitals with a large bed number had greater odds of errors and complications than medium-bed size hospitals, at 1.13 (95% confidence interval, 1.09-1.17), and 1.13 (95% confidence interval, 1.11-1.15), respectively. CONCLUSION: This study identified specific risk factors for errors and complications that can be further examined through quality improvement frameworks to reduce the prevalence of adverse maternal events during cesarean delivery.

Potential Impact of Guidelines for the Prevention of Cesarean Deliveries in a Contemporary Canadian Population.

OBJECTIVE: This study sought to describe how the implementation of recent labour guidelines may affect the cesarean delivery rate in a population in Alberta. METHODS: This retrospective study was conducted on primiparous women who were in labour with singleton term fetuses with cephalic presentation in Alberta from 2007 to 2016 (n = 181 738), and it used data from a perinatal database. Modelled cesarean delivery rates were calculated to determine the potential impact of the recent guidelines on the cesarean delivery rate by using the percentage of cesarean deliveries that occurred outside the threshold of the recent labour guidelines. RESULTS: A total of 21.7% of the cesarean deliveries for dystocia occurred outside of the guidelines related to the first stage of labour arrest for spontaneous labour (n = 9282), and 45.4% occurred outside of the guidelines related to the first stage of labour arrest for induced labours (n = 11 712). A total of 69.0% of the cesarean deliveries for dystocia occurred outside of the failed induction of labour guidelines (n = 4921), and 55.4% occurred outside of the second stage labour arrest guidelines (n = 6632). Assuming that the labour arrest guidelines are effective at reducing the cesarean delivery rate 25% of the time, the cesarean delivery rate for primiparous women in labour would be reduced from 22.5% to 20.7%. Assuming a 75% adherence/effectiveness rate, the cesarean delivery rate would be reduced to 17.1%. CONCLUSION: The recent labour guidelines have the potential to have a substantial impact on the intrapartum cesarean delivery rate in primiparous women with singleton fetuses with cephalic presentation at term if the guidelines are put into practice.

Guidelines for postoperative care in cesarean delivery: Enhanced Recovery After Surgery (ERAS) Society recommendations (part 3).

BACKGROUND: This Enhanced Recovery After Surgery Guideline for postoperative care in cesarean delivery will provide best practice, evidenced-based recommendations for postoperative care with primarily a maternal focus. OBJECTIVE: The pathway process for scheduled and unscheduled cesarean delivery for this Enhanced Recovery After Surgery cesarean delivery guideline will consider time from completion of cesarean delivery until maternal hospital discharge. STUDY DESIGN: The literature search (1966-2017) used Embase and PubMed to search medical subject headings that included "Cesarean Section," "Cesarean Delivery," "Cesarean Section Delivery," and all postoperative Enhanced Recovery After Surgery items. Study selection allowed titles and abstracts to be screened by individual reviewers to identify potentially relevant articles. Metaanalyses, systematic reviews, randomized controlled studies, nonrandomized controlled studies, reviews, and case series were considered for each individual topic. Quality assessment and data analyses evaluated the quality of evidence, and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation system as used and described in previous Enhanced Recovery After Surgery Guidelines. RESULTS: The Enhanced Recovery After Surgery cesarean delivery guideline/pathway has created a pathway for postoperative care. Specifics include sham feeding, nausea and vomiting prevention, postoperative analgesia, nutritional care, glucose control, thromboembolism prophylaxis, early mobilization, urinary drainage, and discharge counseling. A number of elements of postoperative care of women who undergo cesarean delivery are recommended, based on the evidence. CONCLUSION: As the Enhanced Recovery After Surgery cesarean delivery pathway (elements/processes) are studied, implemented, audited, evaluated, and optimized by the maternity care teams, there will be an opportunity for focused and optimized areas of care and recommendations to be further enhanced.

Cyclooxygenase inhibitors for treating preterm labour: What is the molecular evidence? 1.

Preterm birth (<37 weeks of gestation) significantly increases the risk of neonatal mortality and morbidity. As many as half of all preterm births occur following spontaneous preterm labour. Since in such cases there are no known reasons for the initiation of labour, treatment of preterm labour (tocolysis) has sought to stop labour contractions and delay delivery. Despite some success, the use of cyclooxygenase (COX) inhibitors is associated with maternal/fetal side effects, and possibly increased risk of preterm birth. Clinical use of these drugs predates the collection of molecular and biochemical evidence in vitro, examining the expression and activity of COX enzymes in pregnant uterine tissues with and without labour. Such evidence is important to the rationale that COX enzymes are, or are not, appropriate targets for the tocolysis. The current study systematically searched existing scientific evidence to address the hypothesis that COX expression/activity is increased with the onset of human labour, in an effort to determine whether there is a rationale for the use of COX inhibitors as tocolytics. Our review identified 44 studies, but determined that there is insufficient evidence to support or refute a role of COX-1/-2 in the onset of preterm labour that supports COX-targeted tocolysis.

Guidelines for Antenatal and Preoperative care in Cesarean Delivery: Enhanced Recovery After Surgery Society Recommendations (Part 1).

This Enhanced Recovery After Surgery (ERAS) Guideline for perioperative care in cesarean delivery will provide best practice, evidenced-based, recommendations for preoperative, intraoperative, and postoperative phases with, primarily, a maternal focus. The focused pathway process for scheduled and unscheduled cesarean delivery for this ERAS Cesarean Delivery Guideline will consider from the time from decision to operate (starting with the 30-60 minutes before skin incision) to hospital discharge. The literature search (1966-2017) used Embase and PubMed to search medical subject headings that included "Cesarean Section," "Cesarean Section," "Cesarean Section Delivery" and all pre- and intraoperative ERAS items. Study selection allowed titles and abstracts to be screened by individual reviewers to identify potentially relevant articles. Metaanalyses, systematic reviews, randomized controlled studies, nonrandomized controlled studies, reviews, and case series were considered for each individual topic. Quality assessment and data analyses that evaluated the quality of evidence and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation system, as used and described in previous ERAS Guidelines. The ERAS Cesarean Delivery Guideline/Pathway has created a maternal focused pathway (for scheduled and unscheduled surgery starting from 30-60 minutes before skin incision to maternal discharge) with ERAS cesarean delivery consensus recommendations preoperative elements (anesthetic medications, fasting, carbohydrate supplementation, prophylactic antibiotics/skin preparation, ), intraoperative elements (anesthetic management, maternal hypothermia prevention, surgical technique, hysterotomy creation and closure, management of peritoneum, subcutaneous space, and skin closure), perioperative fluid management, and postoperative elements (chewing gum, management of nausea and vomiting, analgesia, timing of food intake, glucose management, antithrombotic prophylaxis, timing of ambulation, urinary management, and timing of maternal and neonate discharge). Limited topics for optimized care and for antenatal education and counselling and the immediate neonatal needs at delivery are discussed. Strong recommendations for element use were given for preoperative (antenatal education and counselling, use of antacids and histamine, H2 receptor antagonists, 2-hour fasting and small meal within 6 hours surgery, antimicrobial prophylaxis and skin preparation/chlorhexidine-alcohol), intraoperative (regional anesthesia, prevention of maternal hypothermia [forced warm air, warmed intravenous fluids, room temperature]), perioperative (fluid management for euvolemia and neonatal immediate care needs that include delayed cord clamping), and postoperative (fluid management to prevent nausea and vomiting, antiemetic use, analgesia with nonsteroidal antiinflammatory drugs/paracetamol, regular diet within 2 hours, tight capillary glucose control, pneumatic compression stocking for venous thromboembolism prophylaxis, immediate removal of urinary catheter). Recommendations against the element use were made for preoperative (maternal sedation, bowel preparation), intraoperative (neonatal oral suctioning or increased inspired oxygen), and postoperative (heparin should not be used routinely venous thromboembolism prophylaxis). Because these ERAS cesarean delivery pathway recommendations (elements/processes) are studied, implemented, audited, evaluated, and optimized by the maternity care teams, this will create an opportunity for the focused and optimized areas of care research with further enhanced care and recommendation.

Guidelines for intraoperative care in cesarean delivery: Enhanced Recovery After Surgery Society Recommendations (Part 2).

The Enhanced Recovery After Surgery Society guideline for intraoperative care in cesarean delivery will provide best practice, evidenced-based, recommendations for intraoperative care, with primarily a maternal focus. The "focused" pathway process for scheduled and unscheduled cesarean delivery for this Enhanced Recovery After Surgery cesarean delivery guideline will consider procedure from the decision to operate (starting with the 30-60 minutes before skin incision) through the surgery. The literature search (1966-2017) used Embase and PubMed to search medical subject headings including "cesarean section," "cesarean section," "cesarean section delivery," and all pre- and intraoperative Enhanced Recovery After Surgery items. Study selection allowed titles and abstracts to be screened by individual reviewers to identify potentially relevant articles. Metaanalyses, systematic reviews, randomized controlled studies, nonrandomized controlled studies, reviews, and case series were considered for each individual topic. Quality assessment and data analyses evaluated the quality of evidence and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation system as used and described in previous Enhanced Recovery After Surgery Society guidelines. The Enhanced Recovery After Surgery cesarean delivery guideline/pathway has created a maternal focused pathway (for scheduled and unscheduled surgery starting from 30-60 minutes before skin incision to maternal discharge) with Enhanced Recovery After Surgery-directed preoperative elements, intraoperative elements, and postoperative elements. Specifics of the intraoperative care included the use of prophylactic antibiotics before the cesarean delivery, appropriate patient warming intraoperatively, blunt expansion of the transverse uterine hysterotomy, skin closure with subcuticular sutures, and delayed cord clamping. A number of specific elements of intraoperative care of women who undergo cesarean delivery are recommended based on the evidence. The Enhanced Recovery After Surgery Society guideline for intraoperative care in cesarean delivery will provide best practice, evidenced-based, recommendations for intraoperative care with primarily a maternal focus. When the cesarean delivery pathway (elements/processes) is studied, implemented, audited, evaluated, and optimized by maternity care teams, this will create an opportunity for the focused and optimized areas of care and recommendations to be further enhanced.

Cesarean delivery in the second stage of labor and the risk of subsequent premature birth.

BACKGROUND: Cesarean delivery is being increasingly used by obstetricians for indicated deliveries in the second stage of labor. Unplanned extension of the uterine incision involving the cervix often occurs with these surgeries. Therefore, we hypothesized that cesarean delivery in the second stage of labor may increase the rate of subsequent spontaneous premature birth. OBJECTIVE: We sought to determine if cesarean delivery in the late first stage of labor or in the second stage of labor increases the risk of a subsequent spontaneous preterm birth. STUDY DESIGN: We conducted a retrospective cohort study of matched first and second births from a large Canadian perinatal database. The primary outcomes were spontaneous premature birth <37 and <32 weeks of gestation in the second birth. The exposure was stage of labor and cervical dilation at the time of the first cesarean delivery. The protocol and analysis plan was registered prior to obtaining data at Open Science Foundation. RESULTS: In total, 189,021 paired first and second births were identified. The risk of spontaneous preterm delivery <37 and <32 weeks of gestation in the second birth was increased when the first birth was by cesarean delivery in the second stage of labor (relative risk, 1.57; 95% confidence interval, 1.43-1.73 and relative risk, 2.12; 95% confidence interval, 1.67-2.68, respectively). The risk of perinatal death in the second birth, excluding congenital anomalies, was also correspondingly increased (relative risk, 1.44; 95% confidence interval, 1.05-1.96). CONCLUSION: Cesarean delivery in second stage of labor was associated with a 2-fold increase in the risk of spontaneous preterm birth <32 weeks of gestation in a subsequent birth. This information may inform management of operative delivery in the second stage.

PGF2α modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways.

Prostaglandin F2α (PGF2α) plays a critical role in the initiation and process of parturition. Since human labor has been described as an inflammatory event, we investigated the role of PGF2α in the inflammatory process using cultured human uterine smooth muscle cells (HUSMCs) isolated from term pregnant women as a model. Using a multiplex assay, HUSMCs treated with PGF2α changed their output of a number of cytokines and chemokines, with a distinct response pattern that differed between HUSMCs isolated from the upper and lower segment region of the uterus. Confirmatory enzyme-linked immunosorbent assays (ELISAs) showed that PGF2α stimulated increased output of interleukin (IL) 1ß, IL6, IL8 (CXCL8) and monocyte chemotactic protein-1 (MCP1, also known as chemokine (c-c motif) ligand 2, CCL2) by HUSMCs isolated from both upper and lower uterine segments. In contrast, PGF2α inhibited tumor necrosis factor α (TNFα) release by HUMSCs from the lower uterine segment while the output of TNFα was undetectable in the upper segment. Small interfering (si) RNA mediated knockdown of the PGF2α receptor prevented the changes in cytokine and chemokine output by the HUSMCs. Since the PGF2α receptor (PTGFR) couples via the Gq protein and subsequently activates the phospholipase C (PLC) and protein kinase C (PKC) signaling pathways, we examined the role of these pathways in PGF2α modulation of the cytokines. Inhibition of PLC and PKC reversed the effects of PGF2α. PGF2α activated multiple signaling pathways including extracellular signal-regulated kinases (ERK) 1/2, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), P38, calcineurin/nuclear factor of activated T-cells (NFAT) and NF-κB signaling. Inhibition of ERK reversed PGF2α-induced IL1ß, IL6 and CCL2 output, while inhibition of PI3K blocked the effect of PGF2α on IL6, CXCL8 and CCL2 output and inhibition of NF-κB reversed PGF2α-induced IL1ß and CCL2 output. NFAT was involved in PGF2α modulation of CCL2 and TNFα output. In conclusion, our results support a role of PGF2α in creating an inflammatory environment during the late stage of human pregnancy.

Regulation of sPLA2-IID in Human Decidua: Insights Into the Complexity of the Prostaglandin Pathway in Labor.

Prostaglandins are implicated in the labor process, yet the precise role and regulation of the prostaglandin pathway remains to be elucidated. The first step in the pathway is cleavage of membrane phospholipids by phospholipase A2 (PLA2). Previous work demonstrated upregulation of secretory PLA2 (sPLA2)-IIA with labor in human myometrium, and recent evidence shows that there are numerous PLA2 isoforms. The present study investigates the potential of additional sPLA2 isoforms during pregnancy and labor. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry were used to determine sPLA2 expression and localization. Results show the presence of sPLA2-IID in amnion, chorion, placenta, decidua, and myometrium. Expression of sPLA2-IID in decidua was significantly decreased in term labor compared to nonlabor patients, whereas no significant labor-associated changes were observed in other gestational tissues. Secretory PLA2-IID was localized within chorion fibroblasts, placenta trophoblasts, decidual cells, and in myometrial smooth muscle cells. In primary decidual cell cultures, interleukin (IL) 10 (IL-10) increased sPLA2-IID messenger RNA (mRNA) expression, while IL-1ß had no effect on sPLA2-IID mRNA expression. In conclusion, decreased expression of sPLA2-IID in the decidua at labor indicates that it is unlikely to contribute to increased prostaglandin production during labor. However, increased expression of sPLA2-IID, induced by IL-10, suggests that sPLA2-IID may play an important anti-inflammatory role at the maternal-fetal interface. Nevertheless, precise functions of sPLA2-IID within the human uterus remain to be determined.

Effects of PGF2α on the expression of uterine activation proteins in pregnant human myometrial cells from upper and lower segment.

CONTEXT: The lower and upper segments of the uterus may play different roles in the process of parturition. The switch from pregnancy to delivery involves changes in expression of uterine activation proteins (UAPs). Prostaglandin (PG) F2α has multiple and complex roles in the birth process in addition to its vital contractile role. OBJECTIVE: The purpose of this study was to investigate whether PGF2α regulates the expression of UAPs in human myometrium and to compare PGF2α actions in lower and upper segments. DESIGN: Cultured human myometrial cells from upper and lower segments were treated with PGF2α. Western blotting was used to determine the levels of connexin 43 (CX-43), prostaglandin endoperoxide synthase-2 (PTGS-2; cyclooxygenase-2), oxytocin receptor (OTR), and PGF2α receptor (PTGFR) in the cells. The small interfering RNA approach was used to knock down PTGFR. RESULTS: PGF2α dose dependently increased CX-43 and PTGS-2 while decreasing PTGFR in upper and lower segments. PGF2α increased OTR in the lower segment while decreasing it in the upper segment. PGF2α lost its effects on PTGS-2 and OTR in PTGFR knockdown cells, but its effect on CX-43 remained. AL8810, a specific antagonist of PTGFR, reversed the actions of PGF2α on UAPs except for CX-43 in the lower segment. Indomethacin reversed the PGF2α-induced effects on CX-43 and PTGS-2, but it did not alter PGF2α-induced PTGFR and OTR expression. The stimulatory effects of PGF2α were enhanced in the presence of IL-1ß, which reversed the inhibitory effect of PGF2α on PTGFR. CONCLUSION: PGF2α regulates UAPs in both upper and lower segment cells through either direct or indirect pathways, indicating that PGF2α uniquely participates in uterine preparation for the onset of labor.

Development and validation of primary human myometrial cell culture models to study pregnancy and labour.

BACKGROUND: The development of the in vitro cell culture model has greatly facilitated the ability to study gene expression and regulation within human tissues. Within the human uterus, the upper (fundal) segment and the lower segment may provide distinct functions throughout pregnancy and during labour. We have established primary cultured human myometrial cells, isolated from both upper and lower segment regions of the pregnant human uterus, and validated them for the purpose of studying human pregnancy and labour. The specific objectives of this study were to monitor the viability and characterize the expression profile using selected cellular, contractile and pregnancy associated markers in the primary cultured human myometrial cells. Labour has been described as an inflammatory process; therefore, the ability of these cells to respond to an inflammatory stimulus was also investigated. METHODS: Myometrial cells isolated from paired upper segment (US) and lower segment (LS) biopsies, obtained from women undergoing Caesarean section deliveries at term prior to the onset of labour, were used to identify expression of; α smooth muscle actin, calponin, caldesmon, connexin 43, cyclo-oxygenase-2 (COX-2), oxytocin receptor, tropomyosin and vimentin, by RT-PCR and/or immunocytochemistry. Interleukin (IL)-1ß was used to treat cells, subsequently expression of COX-2 mRNA and release of interleukin-8 (CXCL8), were measured. ANOVA followed by Bonferroni's multiple comparisons test was performed. RESULTS: We demonstrate that US and LS human myometrial cells stably express all markers examined to at least passage ten (p10). Connexin 43, COX-2 and vimentin mRNA expression were significantly higher in LS cells compared to US cells. Both cell populations respond to IL-1ß, demonstrated by a robust release of CXCL8 and increased expression of COX-2 mRNA from passage one (p1) through to p10. CONCLUSIONS: Isolated primary myometrial cells maintain expression of smooth muscle and pregnancy-associated markers and retain their ability to respond to an inflammatory stimulus. These distinct myometrial cell models will provide a useful tool to investigate mechanisms underlying the process of human labour and the concept of functional regionalization of the pregnant uterus.

Recurrent exophytic meningioma in pregnancy.

BACKGROUND: Meningiomas are slow-growing tumors that may present in pregnancy because of accelerated growth. We present the case of a recurrent meningioma in two separate pregnancies in the same woman. CASE: A 35-year-old woman presented at 30 weeks of gestation with limb weakness, vomiting, and a progressive decreased level of consciousness with an enlarging forehead mass. Imaging revealed a massive extra-axial exophytic tumor. An emergency craniotomy was performed, complicated by massive blood loss. Final pathology showed a grade I meningioma positive for progesterone receptors. Maternal-fetal outcome was good, with return of normal neurologic status and elective delivery at 38 weeks of gestation. CONCLUSION: Pregnancy is associated with accelerated meningioma growth and recurrence. Treatment during pregnancy is possible and requires a multidisciplinary approach.

The risk of diagnostic hysteroscopy in women with endometrial cancer.

OBJECTIVE: We sought to evaluate whether hysteroscopy in patients with endometrial cancer had an effect on disease stage or mortality. STUDY DESIGN: This was a retrospective cohort analysis of data linked between a registry of women diagnosed with endometrial cancer and physician billing data on hysteroscopy. RESULTS: A 99.8% match rate was obtained. Eighty-five percent of cases had complete data on staging. Of these 1972 cases, 672 (34.1%) had undergone hysteroscopy. There was no difference in stage III disease between the hysteroscopy (7.1%) vs no hysteroscopy (6.5%) group (P = .38). There was also no difference in death rates, 13.2% vs 15.2% (P = .25), or in the proportion of women dying of female genital organ cancer, 46.1% vs 42.1% (P = .53), respectively. CONCLUSION: Hysteroscopy is not associated with a higher rate of stage III disease or mortality. It allows for accurate diagnosis with direct visualization and biopsy, and should be considered a safe diagnostic tool.

Endocrine disruptors and spontaneous premature labor: a case control study.

BACKGROUND: Premature labor is a poorly understood condition. Estrogen is thought to play a key role and therefore the labor process may be affected by endocrine disruptors. We sought to determine whether or not an environmental toxicant, DDE, or dietary derived endocrine disruptors, daidzein and genistein, are associated with spontaneous preterm labor. METHODS: Cases were defined as primiparous patients having a preterm delivery at or before 35 weeks following the spontaneous onset of labor. Controls were defined as primiparous women who delivered on the same day as the cases but at term gestation. Over approximately 1 year, 26 cases and 52 controls were recruited. Subjects agreed to have blood tests on day one postpartum for DDE and for the phytoestrogens genistein and daidzein. RESULTS: The mean concentration of DDE was similar in the case and control groups: 4.29 vs 4.32 ng/g lipid p = .85. In the case group, 13/26 had detectable levels of daidzein (range 0.20 - 1.56 ng/ml) compared to 25/52 controls (range 0.21 - 3.26 ng/ml). The mean concentration of daidzein was similar in cases compared to controls: 0.30 vs .34 ng/ml p = 0.91. Of the case group,14/26 had detectable levels of genistein (range 0.20 - 2.19 ng/ml) compared to 32/52 controls (range 0.21 - 2.55 ng/ml). The mean concentration of genistein was similar in cases compared to controls: 0.39 vs 0.31 ng/ml, p = 0.61. CONCLUSION: The serum levels of DDE in this population were found to be low. There appears to be no relationship between serum concentrations of DDE, daidzein, and genistein and spontaneous preterm labor in our population. The inability to identify an effect may be related to the comparatively low concentrations of DDE in our population and the rapid and variable reduction of phytoestrogens from women in labor.